Role of mTOR signaling in intestinal cell migration.

An early signaling event activated by amino acids and growth factors in many cell types is the phosphorylation of the mammalian target of rapamycin (mTOR; FRAP), which is functionally linked to ribosomal protein s6 kinase (p70(s6k)), a kinase that plays a critical regulatory role in the translation of mRNAs and protein synthesis. We previously showed that intestinal cell migration, the initial event in epithelial restitution, is enhanced by l-arginine (ARG). In this study, we used amino acids as prototypic activators of mTOR and ARG, IGF-1, or serum as recognized stimulators of intestinal cell migration. We found that 1) protein synthesis is required for intestinal cell migration, 2) mTOR/p70(s6k) pathway inhibitors (rapamycin, wortmannin, and intracellular Ca(2+) chelation) inhibit cell migration, 3) ARG activates migration and mTOR/p70(s6k) (but not ERK-2) in migrating enterocytes, and 4) immunocytochemistry reveals abundant p70(s6k) staining in cytoplasm, whereas phospho-p70(s6k) is virtually all intranuclear in resting cells but redistributes to the periphery on activation by ARG. We conclude that mTOR/p70(s6k) signaling is essential to intestinal cell migration, is activated by ARG, involves both nuclear and cytoplasmic events, and may play a role in intestinal repair.